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ANESTHETIC PHARMACOLOGY

Landiolol, an Ultra–Short-Acting ß1-Adrenoceptor Antagonist, Does Not Alter the Minimum Alveolar Anesthetic Concentration of Isoflurane in a Swine Model

From the Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, Handayama, Hamamatsu, Japan.

Address correspondence and reprint requests to Tadayoshi Kurita, MD, Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. Address e-mail to tadkur{at}hama-med.ac.jp.

	Abstract

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BACKGROUND: We previously reported that landiolol, an ultra–short-acting ß1-adrenoceptor antagonist, does not alter the electroencephalographic effect of isoflurane. Here, we investigated the influence of landiolol on the minimum alveolar anesthetic concentration (MAC) of isoflurane required to prevent movement in response to a noxious stimulus in 50% of subjects.

METHODS: Ten swine (29.0 ± 3.4 kg) were anesthetized by inhalation of isoflurane. MAC was determined using the dewclaw clamp technique, in which movement in response to clamping is recorded. After determination of MAC in the baseline period, an infusion of landiolol (0.125 mg · kg^–1 · min^–1 for 1 min, then 0.04 mg · kg^–1 · min^–1) was started. After a 20-min stabilization period, MAC was again assessed (0.04 mg · kg^–1 · min^–1 landiolol). The infusion of landiolol was then increased from 0.04 to 0.2 mg · kg^–1 · min^–1, and after a 20-min stabilization period, MAC was again assessed (0.2 mg · kg^–1 · min^–1 landiolol). Finally, the infusion of landiolol was stopped, and after a 20-min stabilization period, MAC was assessed for a fourth time (Baseline 2).

RESULTS: Landiolol clearly attenuated the increases in heart rate and mean arterial blood pressure that occurred in response to the dewclaw clamp, but did not alter the MAC of isoflurane.

CONCLUSIONS: Landiolol does not alter the antinociceptive effect of isoflurane. This result, combined with that from our previous work, also suggests that landiolol does not influence the anesthetic potency of inhaled anesthetics.

	Introduction

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The effect of ß-adrenoceptor antagonists on anesthetic requirements and electroencephalographic (EEG) responses is a controversial subject (1–10). Several studies have suggested that these drugs have an anesthetic-sparing effect during general anesthesia (1–3), whereas others have reported that no changes in anesthetic requirements are associated with the administration of ß-adrenoceptor antagonists (4,5). Most of these studies have used esmolol, a short-acting ß1-adrenoceptor antagonist, since this drug is commonly used in anesthesia to attenuate hemodynamic responses.

Landiolol hydrochloride is a new, highly cardioselective, and ultra–short-acting ß1-adrenoceptor antagonist with a potency ratio (ß1/ß2) of 255, compared with 33 for esmolol and 0.68 for propranolol (11). In Japan, landiolol is widely used during anesthesia. We previously examined the influence of landiolol on the EEG effect of isoflurane in a swine model and concluded that landiolol does not alter the hypnotic effect of isoflurane (12). However, the EEG only reflects the influence of landiolol on hypnosis, not on immobility in response to noxious stimuli, which is also of importance for the potency of an inhaled anesthetic. The motor response to a noxious stimulus is primarily mediated by subcortical structures, especially those in the spinal cord (13–15), and EEG parameters do not directly reflect the activity of these structures. It is therefore possible that the influence of landiolol on EEG parameters and motor response could be different.

We conducted the present study to investigate the influence of landiolol on the minimum alveolar anesthetic concentration (MAC) of inhaled anesthetics. Since landiolol is ionized and relatively hydrophilic, it has limited access to the central nervous system and is unlikely to have a significant action on spinal neurons responsible for mobility. Hence, we hypothesized that landiolol would not alter the MAC of isoflurane, similar to its lack of influence on the hypnotic effect of isoflurane.

	METHODS

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Animal Preparation
This study was approved by the Committee on Animal Research, Hamamatsu University School of Medicine, Hamamatsu, Japan. Ten pigs (body-weight range: 24.7–34.1 kg, mean ± sd = 29.0 ± 3.4 kg) were used in the study. General anesthesia was induced by isoflurane inhalation (5%) in oxygen at 6 L/min using a standard animal mask. After tracheostomy, the lungs of the pigs were mechanically ventilated, and anesthesia was maintained with a 2% end-tidal concentration of isoflurane in an oxygen–air mixture (oxygen:air = 3:3 L/min). The tidal volume was initially set to approximately 10 mL/kg and the ventilation rate 25 breaths/min. Expiratory gases were analyzed using a Capnomac Ultima (ULT-V-31-04, Datex-Ohmeda, Helsinki, Finland) throughout the study. The ventilator was adjusted to keep the end-tidal carbon dioxide between 35 and 45 mm Hg during the preparation period, and this setting was maintained throughout the study. Lead II of an electrocardiogram was monitored using three cutaneous electrodes. A pulmonary artery catheter (5 F, 4 lumen, Nihon Kohden, Tokyo, Japan) and a central venous catheter (16-gauge) were inserted via the right jugular vein, and another catheter (16-gauge) was placed in the right femoral artery for measuring mean arterial blood pressure (MAP). The blood temperature was measured using a pulmonary artery catheter and maintained between 39.0°C and 40.0°C.

Experimental Protocol
Baseline measurements were taken 30 min after completion of animal preparation. MAC was assessed beginning at 2% end-tidal concentration (baseline conditions). After determination of MAC under baseline conditions and return of the end-tidal isoflurane concentration to 2%, landiolol hydrochloride was administered with an infusion pump via a central venous catheter at a rate of 0.125 mg · kg^–1 · min^–1 for 1 min and then at 0.04 mg · kg^–1 · min^–1 (a comparable dose to that administered to humans). After 20 min, and after confirming hemodynamic stability, MAC (0.04 mg · kg^–1 · min^–1 landiolol conditions) was again assessed. After determination of MAC at 0.04 mg · kg^–1 · min^–1 landiolol and return of the end-tidal isoflurane concentration to 2%, the landiolol hydrochloride infusion rate was increased from 0.04 to 0.2 mg · kg^–1 · min^–1. After 20 min, MAC was assessed again (0.2 mg · kg^–1 · min^–1 landiolol conditions). After determination of MAC under these conditions and return of the end-tidal isoflurane concentration to 2%, the infusion of landiolol was stopped. After 20 min, and after confirming hemodynamic recovery, MAC was again assessed (Baseline 2 conditions). Heart rate (HR), MAP, mean pulmonary arterial pressure (MPA), central venous pressure (CVP), and cardiac output (CO) were recorded at 2% end-tidal isoflurane concentration under all conditions. CO was determined with a thermodilution computer (Cardiac Output Computer, MTC6210, Nihon Kohden, Tokyo, Japan) using 5 mL cold 5% glucose injected into the right atrium. For each condition, CO measurements were made four times, and the mean of the last three values was recorded as the CO.

Determination of MAC
MAC was assessed under each of the four conditions in each animal, starting from a 2% end-tidal concentration of isoflurane. The starting value was determined with reference to the MAC value reported by Eger et al. (16). A supramaximal pain stimulus was created by application of a clamp to the dewclaw for 60 s, and the presence or absence of a withdrawal reaction during the 60-s period was recorded. A positive reaction was defined as either a withdrawal of the clamped foot or as a gross movement of another leg or the head. If a positive response occurred, the end-tidal concentration was increased by 0.2%. In exceptional cases in which a positive response occurred but hemodynamic changes were minimal, the end-tidal concentration was increased by 0.1%. After another equilibration period of 20 min, a second noxious stimulus was applied and this protocol was repeated until there was no motor reaction. If no motor response was elicited by the noxious stimulus, the end-tidal concentration was decreased by 0.2%. In exceptional cases in which no motor response was elicited, but hemodynamic changes were large, the end-tidal concentration was decreased by 0.1%, and the protocol was repeated until a movement response occurred. The study protocol was considered complete after a change in movement response from positive to negative or vice versa. MAC was calculated as the average of the highest isoflurane concentration at which movement occurred and the lowest concentration at which movement was suppressed. The maximum values of HR and MAP during the period of dewclaw clamping for 60 s were recorded, and the percentage increases in these variables from the respective preclamp values were calculated as follows: 100 x (maximum HR or MAP during dewclaw clamping for 60 s – preclamp HR or MAP)/preclamp HR or MAP.

Statistical Analysis
Data are expressed as mean values ± sd. HR, MAP, MPA, CVP, and CO at 2% end-tidal isoflurane concentration and MAC for each state were analyzed using a repeated-measures one-way analysis of variance (ANOVA). The percentage increases in HR and MAP for each state were also analyzed using ANOVA. If the ANOVA indicated significance, Scheff é F-test for multiple comparisons was performed. P values <0.05 were considered to be statistically significant.

	RESULTS

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Averaged hemodynamic variables at 2% end-tidal isoflurane concentration for each state are shown in Table 1. Landiolol decreased HR, MAP and CO, and HR and MAP were significantly decreased at 0.2 mg · kg^–1 · min^–1 landiolol compared with the respective values at baseline. However, hemodynamic changes were modest without stimulation: MAP and CO decreased by <10%, even at 0.2 mg · kg^–1 · min^–1 landiolol (Table 1). The hemodynamic changes showed a reversal after termination of landiolol administration. MPA and CVP did not change upon landiolol administration.

Landiolol attenuated the increase in HR that occurred in response to the dewclaw clamp. The percentage increase in HR at end-tidal concentrations close to MAC (the highest isoflurane concentration at which movement occurred and the lowest concentration at which movement was suppressed) for each state were 6.5% ± 5.2% at baseline, 2.0% ± 2.0% at 0.04 mg · kg^–1 · min^–1 landiolol, 1.1% ± 1.1% at 0.2 mg · kg^–1 · min^–1 landiolol, and 6.5% ± 7.1% at Baseline 2 (there were significant differences between the two baseline conditions and the two doses of landiolol); these data are shown for baseline and 0.2 mg · kg^–1 · min^–1 landiolol in Figures 1A and B, respectively. In all animals, the percentage increases in HR were <17.2% at baseline and <3.6% with 0.2 mg · kg^–1 · min^–1 landiolol administration.

View larger version (17K): [in this window] [in a new window]   Figure 1. The percentage increase in heart rate (HR) (100 x (maximum HR during dewclaw clamping for 60 s – preclamp HR)/preclamp HR) close to minimum alveolar anesthetic concentration at baseline (A) and with 0.2 mg · kg–1 · min–1 landiolol administration (B). Dotted circles represent the highest isoflurane concentration at which movement occurred, and open circles represent the lowest concentration at which movement was suppressed.

Landiolol also attenuated the increase in MAP in response to the dewclaw clamp. The percentage increases in MAP at end-tidal concentrations close to MAC (the highest isoflurane concentration at which movement occurred and the lowest concentration at which movement was suppressed) for each state were 14.0% ± 12.4% at baseline, 8.4% ± 7.1% at 0.04 mg · kg^–1 · min^–1 landiolol, 6.6% ± 3.6% at 0.2 mg · kg^–1 · min^–1 landiolol, and 21.3% ± 16.0% at Baseline 2 (there were significant differences between both doses of landiolol and Baseline 2); these data are shown for baseline and 0.2 mg · kg^–1 · min^–1 landiolol in Figures 2A and B, respectively. In all animals, the percentage increases in MAP were <39.3% at baseline and <14% with 0.2 mg · kg^–1 · min^–1 landiolol administration.

View larger version (19K): [in this window] [in a new window]   Figure 2. The percentage increase in mean arterial blood pressure (MAP) (100 x (maximum MAP during dewclaw clamping for 60 s – preclamp MAP)/preclamp MAP) close to minimum alveolar anesthetic concentration at baseline (A) and with 0.2 mg · kg–1 · min–1 landiolol administration (B). Dotted circles represent the highest isoflurane concentration at which movement occurred, and open circles represent the lowest concentration at which movement was suppressed.

MAC values for each condition in all animals are shown in Figure 3. The mean MAC values for each condition were 1.92% ± 0.18% at baseline, 2.08% ± 0.30% at 0.04 mg · kg^–1 · min^–1 landiolol, 1.91% ± 0.28% at 0.2 mg · kg^–1 · min^–1 landiolol, and 1.94% ± 0.28% at Baseline 2, showing that landiolol did not significantly alter the MAC value of isoflurane.

View larger version (12K): [in this window] [in a new window]   Figure 3. Minimum alveolar anesthetic concentrations of isoflurane under different conditions. Open circles represent the mean values.

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
We investigated the influence of landiolol, an ultra–short-acting ß1-adrenoceptor antagonist, on the MAC of isoflurane. The results show that landiolol does not influence the MAC of isoflurane and suggest that landiolol has no effect on the antinociceptive effect of isoflurane.

We have recently examined the influence of landiolol on the EEG effect of isoflurane in a swine model, and concluded that landiolol does not alter the hypnotic effect of isoflurane (12). However, the EEG effect only addresses the influence of landiolol on hypnosis, and does not address the effect on immobility in response to noxious stimuli, which is also important for potency of an inhaled anesthetic. In this context, Johansen et al. (2) found that even high-dose esmolol has no effect on the isoflurane requirement for skin incision. Furthermore, Coloma et al. (17) compared the effect of esmolol and remifentanil infusion on intraoperative hemodynamic stability and early recovery after outpatient laparoscopic surgery when administered as IV adjuvants during desflurane anesthesia. These authors found that use of esmolol during desflurane anesthesia was an acceptable alternative to remifentanil for maintaining hemodynamic stability; however, the mivacurium requirement was larger with esmolol. These results are consistent with the present study, and suggest that short-acting ß1-adrenoceptor antagonists cannot be used as an alternative to opioids for increasing the threshold of movement in response to noxious stimuli during inhaled anesthesia. Oda et al. (8) have shown that both esmolol and landiolol suppress the hemodynamic and bispectral index responses in tracheal intubation under 1 MAC sevoflurane anesthesia. The movement response to tracheal intubation was not examined because vecuronium was used during induction of anesthesia, but we speculate that this response would not have differed from the control group (no esmolol or landiolol).

ß-Adrenoceptor antagonists have been used for many years to control perioperative hemodynamic responses, and esmolol, a short-acting ß1-antagonist, is commonly used in anesthesia to attenuate the stress response to tracheal intubation (7,8), to control postoperative hypertension, and to manage unstable coronary syndromes and tachyarrhythmias (18). In the present study, landiolol clearly attenuated the increases in HR and MAP in response to dewclaw clamping at end-tidal concentrations close to MAC (Figs. 1 and 2), although MAC was unchanged. This result suggests that in practice it will be difficult to evaluate the anesthetic depth from hemodynamic changes in response to noxious stimuli, although movement may be observed. According to the relationship between MAC-BAR (MAC required for blockade of the adrenergic response to a noxious stimulus in 50% of subjects) and MAC for inhaled anesthetics, sympathetic responses were observed before somatic responses with decreasing anesthetic depth, except with administration of a high opioid dose (19). Sympathetic responses could be useful for clinicians to identify inadequate anesthesia before movement, and to adjust the anesthetic dose in response to noxious stimuli. Although short-acting ß1-adrenoceptor antagonists are effective for suppression of harmful hemodynamic responses, they may also suppress useful hemodynamic responses.

Our results demonstrate that landiolol does not alter the potency of isoflurane for producing sedation and immobilization. Harris et al. (20) have recently demonstrated that propofol and sevoflurane interact in a simple additive manner to produce loss of consciousness and immobility upon surgical incision, suggesting a common mechanism or a single site of action for these anesthetics. If both inhaled anesthetics and some IV sedative drugs act through the -aminobutyric acid Type A receptor, the pharmacodynamics of these drugs may also be unaffected by landiolol; therefore, any increased effects of these drugs in the presence of short-acting ß1-adrenoceptor antagonist is likely to be due to alteration of the pharmacokinetics.

Some limitations of the study need to be addressed. Since landiolol is a hydrophilic and highly ß1-selective adrenoceptor antagonist, as is esmolol, it may not readily cross the blood–brain barrier and it has a small ß2-adrenoceptor antagonistic effect. In contrast, ß-adrenoceptor antagonists that show relatively high penetration of the blood–brain barrier and/or a lower ß1/ß2 potency ratio might influence the potency of inhaled anesthetics. Furthermore, a time-control study of MAC in the absence of landiolol was not performed, and it is possible that repetitive noxious stimuli during MAC assessment might influence subsequent MAC determinations. In addition, although we used doses of landiolol comparable with that administered to humans and five-fold the human dose, the distribution of ß-adrenoceptors in swine may differ from that in humans; therefore, ß-adrenoceptor antagonists may not necessarily produce the same effects in swine and humans. Finally, the results of the study were negative, and the power of the study was less than the minimum power of 80% required to accept the null hypothesis with certainty; therefore, a Type II error cannot be excluded. Within these limitations, our results show that landiolol alters neither the hypnotic effect nor the antinociceptive effect of isoflurane. Although further investigation using other ß-adrenoceptor antagonists with different pharmacologic characteristics is necessary, our results indicate that short-acting ß1-adrenoceptor antagonists do not influence the potency of inhaled anesthetics.

	Footnotes

 
Accepted for publication May 24, 2007.

Landiolol hydrochloride was provided by ONO Pharmaceutical Co. Ltd., and other support was provided from departmental sources.

	REFERENCES

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Kurita, T. Articles by Sato, S. Search for Related Content PubMed PubMed Citation Articles by Kurita, T. Articles by Sato, S. Related Collections Preclinical Pharmacology Pharmacology